Synergic Effects of β-Estradiol and Erythromycin on hERG Currents
Synergic Effects of β-Estradiol and Erythromycin on hERG Currents
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DOI：
10.1007/s00232-011-9360-z
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发表时间：
2011-05-01
影响因子：
2.4
通讯作者：
Kawano, Seiko
中科院分区：
文献类型：
--
作者：
Ando, Fumiaki;Kuruma, Akinori;Kawano, Seiko
女性中长QT综合征（LQTS）和药物诱导的尖端扭转型室性心动过速（TDP）的发生率高于男性。虽然性腺类固醇激素被认为在心脏电生理特性的性别差异中发挥重要作用，但性别差异的潜在机制尚未完全了解。特别是I-Kr，它包括动作电位的复极化阶段，尚未很好地了解性激素对其的调节。为了评估这一点，我们研究了女性性激素β-雌二醇对人ether-a-go-go相关基因（hERG）编码的钾电流的影响，该基因在人胚肾-293（HEK）细胞中稳定表达。我们证明，hERG电流被β-雌二醇最大抑制至对照的62%，IC 50为1.3 μ M，Hill系数为0.87，这可能解释了LQTS中的性别相关差异。我们还研究了雌激素是否调制药物诱导的hERG电流的阻断作用。同时应用10 μ M红霉素（已知其可阻断hERG电流，但低剂量时不阻断），β-雌二醇对hERG电流的阻断作用增强。也就是说，10 μ M红霉素对hERG电流的抑制最大为对照的45.8%，IC 50为59 nM（P < 0.02）。我们得出结论，β-雌二醇对hERG电流的显著阻断可能是LQTS性别相关差异的原因，β-雌二醇和红霉素的协同作用表明女性药物诱导TDP的风险高于男性。
The incidence rates of long QT syndrome (LQTS) and drug-induced torsades de pointes (TDP) are higher in women than men. Although gonadal steroids are assumed to play an important role in the gender-based differences in cardiac electrophysiological properties, the underlying mechanisms of the gender-based differences are not fully understood. In particular I-Kr, which comprises the repolarization phase of the action potential, has not been well understood in its modulation by sex hormones. To assess this, we examined the effects of the female sex hormone beta-estradiol on the human ether-a-go-go-related gene (hERG)-encoded potassium current stably expressed in human embryonic kidney-293 (HEK) cells. We demonstrated that hERG currents were inhibited by beta-estradiol maximally to 62% of control with an IC50 of 1.3 mu M and a Hill coefficient of 0.87, which might account for the sex-related differences in LQTS. We also examined whether estrogen modulated drug-induced blocking effects on hERG currents or not. With simultaneous application of 10 mu M erythromycin, which is known to block hERG currents but not in low doses, the blocking effects of beta-estradiol on hERG currents were enhanced. Namely, hERG currents were inhibited maximally to 45.8% of control with an IC50 of 59 nM (P < 0.02) by beta-estradiol with 10 mu M erythromycin. We conclude here that a significant block of hERG currents by beta-estradiol may account for the sex-related differences in LQTS and the synergic effects of beta-estradiol and erythromycin indicate a higher risk of drug-induced TDP in women than men.